PFIZER INC. PROPRIETARY DRUG NAME /GENERIC DRUG NAME: Cerebyx / Fosphenytoin Sodium

Transcription

1 PFIZER INC These results are supplied for informational purposes only. Prescribing decisions should be made based on the approved package insert. For publications based on this study, see associated bibliography. PROPRIETARY DRUG NAME /GENERIC DRUG NAME: Cerebyx / Fosphenytoin Sodium PROTOCOL NO.: PROTOCOL TITLE: An Open-Label, Safety, Tolerance, and Pharmacokinetic Study of Intravenous and Intramuscular Fosphenytoin (Cerebyx ) in Children (Protocol ) Study Centers: This study was conducted at 21 centers in the United States (US). Study Initiation Date and Primary Completion or Completion Dates: Study Initiation Date = 18 September 1996; Completion Date = 08 November 1997; Primary Completion Date = Insufficient information Phase of Development: Phase 3 Study Objective: The objective of this study was to evaluate the safety, tolerance, and pharmacokinetics (PK) of intravenous (IV) and intramuscular (IM) fosphenytoin administered as loading and maintenance doses in pediatric subjects, ranging in age from birth (neonates) through 16 years. METHODS Study Design: This was an open-label, multicenter, Phase 3 clinical study that evaluated the safety, tolerance, and PK of IV and IM fosphenytoin in children for the treatment or prophylaxis of seizures. Subjects of either sex and any race, not older than 16 years of age were included in the study. Subjects were treated with study drug via IV or IM injection. Subjects were given optional maintenance doses for up to 14 days. Subjects were evaluated 12 to 24 hours after the last dose of study medication at a follow-up visit. Number of Subjects (Planned and Analyzed): Between 60 and 100 subjects were planned. A total of 113 subjects were enrolled to receive IV and/or IM fosphenytoin. Two subjects were entered into the study on 2 separate occasions, and both subjects received an IV fosphenytoin loading dose on their initial entry and an IM loading dose on their second entry. Therefore, a total of 115 subjects were exposed to fosphenytoin. All subjects were analyzed for safety. Diagnosis and Main Criteria for Inclusion: Subjects who met the following criteria were entered into the study: either sex, any race, and not older than 16 years of age, those who required a parenteral loading dose of phenytoin for the treatment or prophylaxis of seizures, and had a legal guardian who understood the nature of the study and provided written Page 1

2 informed consent. Exclusions included: subjects with a known hypersensitivity to hydantoins, those with a serious medical condition likely to interfere with the study or expose the subject to increased risk, and those currently taking or who had taken an investigational agent within the past 30 days. Study Treatment: Fosphenytoin was administered as an open-label IV and/or IM solution. Subjects were given an initial loading dose (10 to 20 mg/kg) of IV or IM fosphenytoin. IV doses were infused at a rate of 1 to 3 mg/kg/min (maximum 150 mg/min). IM doses were administered as single or multiple injections. Subjects were given optional maintenance doses for up to 14 days. Efficacy Evaluations: Efficacy analyses were not planned or conducted in this study; however, the number and type of seizures experienced from 7 days prior to screening (or from birth if age <7 days) until follow-up were recorded. Pharmacokinetic Evaluations: Serial blood samples were obtained following fosphenytoin loading dose administration and were analyzed to characterize plasma total fosphenytoin, free (unbound) fosphenytoin, total phenytoin, and free phenytoin concentrations. Daily trough blood samples were obtained to characterize plasma total phenytoin concentrations during maintenance therapy. Safety Evaluations: Safety was assessed by evaluation of the frequency and intensity of adverse events (AEs) following fosphenytoin administration, and changes in neurological and physical examinations, vital signs, electrocardiogram (ECG), clinical laboratory determinations, and plasma phenytoin concentrations. In addition, clinical laboratory parameters plasma phosphate and ionized calcium were evaluated following fosphenytoin loading dose administration. Plasma formate was evaluated following fosphenytoin loading and maintenance doses. Investigators performed evaluations of erythema, swelling, tenderness, necrosis, and bruising at the IV/IM site at 0, 1, and 2 hours after the loading dose, and again at the follow-up visit, using a scale from 0 to 3 (0 = None, 1 = Mild, 2 = Moderate, 3 = Severe). Infusion/injection-site evaluations were also performed immediately before and at 0 and 1 hour after each maintenance dose, using the same scale. Signs or symptoms following specific infusion/injection-site evaluations were described as a reaction when present or no reaction when not present. Statistical Methods: The sample size of 60 to 100 subjects was chosen as a reasonable sample for the evaluation of the safety and tolerance of IV and IM fosphenytoin administered to pediatric subjects through 16 years of age. AEs were summarized by body system and age group, using descriptive statistics. Vital sign changes and infusion-site evaluations were summarized using descriptive statistics. The incidence of seizure within 7 days prior to and during the study was summarized. Page 2

3 RESULTS Subject Disposition and Demography: One hundred and thirteen subjects (63 males and 50 females) were enrolled in this study. All 113 subjects who were enrolled received treatment. Of the 113 subjects treated in the study, 111 (98.2%) completed the study. A summary of demographic characteristics for subjects in this study is presented in Table 1. Table 1. Demographic Characteristics Characteristic Neonates N = 21 Infants N = 33 Number of Subjects (N) Children N = 45 Adolescents N = 14 Total N = 113 Sex, N (%) Male 9 (42.9) 22 (66.7) 24 (53.3) 8 (57.1) 63 (55.8) Female 12 (57.1) 11 (33.3) 21 (46.7) 6 (42.9) 50 (44.2) Race, N (%) White 10 (47.6) 16 (48.5) 22 (48.9) 5 (35.7) 53 (46.9) Black 5 (23.8) 9 (27.3) 16 (35.6) 7 (50.0) 37 (32.7) Hispanic 5 (23.8) 8 (24.2) 5 (11.1) 1 (7.1) 19 (16.8) Asian 0 (0.0) 0 (0.0) 0 (0.0) 1 (7.1) 1 (0.9) Other 1 (4.8) 0 (0.0) 2 (4.4) 0 (0.0) 3 (2.7) Age (unit) (days) (months) (yr) (yr) -- Mean (SD) 10.2 (9.9) 10.5 (7.3) 5.7 (2.5) 14.5 (1.6) -- Range Weight (Kg) Mean (SD) 2.77 (1.2) 8.39 (3.6) (7.6) (12.0) -- Range Primary Reason for Treatment, N (%) Treatment of Seizures 20 (95.2) 26 (78.8) 21 (46.7) 9 (64.3) 76 (67.3) Prophylaxis of Seizures 1 (4.8) 7 (21.2) 18 (40.0) 5 (35.7) 31 (27.4) Status Epilepticus 0 (0.0) 0 (0.0) 4 (8.9) 0 (0.0) 4 (3.5) Other 0 (0.0) 0 (0.0) 2 (4.4) 0 (0.0) 2 (1.8) Baseline Plasma Phenytoin Concentration N (%) Measurable Pre-Existing Concentration No Measurable Pre- Existing Concentration Missing Concentration Information 4 (19.0) 7 (21.2) 11 (24.4) 6 (42.9) 28 (24.8) 17 (81.0) 24 (72.7) 34 (75.6) 8 (57.1) 83 (73.5) 0 (0.0) 2 (6.1) 0 (0.0) 0 (0.0) 2 (1.8) Efficacy Results: There were no efficacy evaluations in this study. Pharmacokinetic Results: Fosphenytoin was rapidly and consistently converted to phenytoin in pediatric subjects from birth through 16 years, including premature newborns. Fosphenytoin loading dose administration produced therapeutic plasma total and free phenytoin concentrations rapidly and consistently, independent of age or route of administration. Maintenance fosphenytoin dosing can be used to maintain therapeutic phenytoin concentrations. The PK of fosphenytoin in pediatric and adult subjects appeared Page 3

4 to be the same, allowing use of the same loading dose on a milligram per kilogram basis independent of subjects age. Safety Results: The overall incidence and types of AEs were generally similar across all age groups. The majority of subjects had mild to moderate events. The types of AEs that occurred were similar to those expected with phenytoin therapy or the subject s medical condition (eg, postoperative status) and consistent with previous studies of fosphenytoin in adult subjects. Nystagmus, vomiting, ataxia, fever, somnolence, nervousness, and pruritus were the most frequent AEs, occurring in 5% of all pediatric subjects treated with fosphenytoin. One serious AE ([SAE] cardiac arrest) occurred in a premature critically ill neonate, which led to the withdrawal and subsequent death of the subject. Neither the SAE nor the death was considered related to treatment with fosphenytoin. One additional premature neonate was withdrawn from the study due to an AE (elevated plasma phenytoin concentration). An overview of AEs is summarized in Table 2. Page 4

5 Table 2. Overview of Adverse Events Number of Subjects Neonates N = 21 Infants N = 33 Children N = 45 Adolescents N = 14 Total N = 113 Number (%) of Subjects with AEs All AEs 11 (52.4) 23 (69.7) 27(60.0) 11 (78.6) 72 (63.7) Associated AEs a 4 (19.0) 14 (42.4) 18 (40.0) 9 (64.3) 45 (39.8) Number of AEs All AEs Associated AEs AEs by Sex, N (%) All AEs Male 4 (44.4) 14 (63.6) 12 (50.0) 5 (62.5) 35 (55.6) Female 7 (58.3) 9 (81.8) 15 (71.4) 6 (100.0) 37 (74.0) AEs by Race, N (%) All AEs White 4 (40.0) 11 (68.8) 13 (59.1) 5 (100.0) 33 (62.3) Black 3 (60.0) 6 (66.7) 10 (62.5) 5 (71.4) 24 (64.9) Other 4 (66.7) 6 (75.0) 4 (57.1) 1 (50.0) 15 (65.2) Associated AEs White 3 (30.0) 5 (31.3) 9 (40.9) 3 (60.0) 20 (37.7) Black 1 (20.0) 4 (44.4) 6 (37.5) 5 (71.4) 16 (43.2) Other 0 (0.0) 5 (62.5) 3 (42.9) 1 (50.0) 9 (39.1) Maximum Intensity of AEs, N (%) All AEs Mild 8 (38.1) 14 (42.4) 17(37.8) 9 (64.3) 48 (42.5) Moderate 0 (0.0) 9 (27.3) 10 (22.2) 2 (14.3) 21 (18.6) Severe 3 (14.3) 0 (0.0) 0 (0.0) 0 (0.0) 3 (2.7) Associated AEs Mild 4 (19.0) 12 (36.4) 12 (26.7) 8 (57.1) 36 (31.9) Moderate 0 (0.0) 2 (6.1) 6 (13.3) 1 (7.1) 9 (8.0) Severe 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Deaths, N (%) 1 (4.8) 0 (0.0) 0 (0.0) 0 (0.0) 1 b (0.9) Serious AEs, N (%) 1 (4.8) 0 (0.0) 0 (0.0) 0 (0.0) 1 b (0.9) Did Not Complete 2 (9.5) 0 (0.0) 0 (0.0) 0 (0.0) 2 (1.8) a An adverse event was defined to be associated with study treatment if the investigator considered it to be definitely, probably, or possibly related, or if there was insufficient information to determine the relationship. b Same subject c AE = Adverse event The majority of subjects (89%) had no reaction at the infusion site following the IV loading dose. Nine of the 84 subjects with evaluable infusion data had mild to moderate bruising, tenderness, erythema, and/or swelling; 1 of these subjects also had severe erythema. No necrosis was reported. Of the 24 subjects with evaluable IM loading dose data, 10 showed no reaction to the IM injection and 14 had mostly mild to moderate swelling, tenderness, or erythema; there were no reports of severe or necrotic reactions. Infusion/injection site reactions following IV/IM maintenance dosing were generally similar across all age groups to those observed during loading dose administration. Page 5

6 CONCLUSIONS: Fosphenytoin administered intravenously or intramuscularly as either loading or maintenance doses was safe and well tolerated in pediatric subjects from birth through 16 years of age, including premature newborns. Fosphenytoin is rapidly, consistently, and predictably converted to phenytoin in all ages of pediatric subjects. The safety profile and pharmacokinetics of fosphenytoin in pediatric and adult subjects appear similar, allowing the same loading dose on a milligram per kilogram basis independent of subjects age. Fosphenytoin can be used to maintain therapeutic phenytoin concentrations and should be individualized based on clinical response and plasma phenytoin concentrations. Page 6